Purification Strategies to Process 5 g/L Titers of Monoclonal Antibodies - Altering the order of operations, using new resins, and increasing dynamic binding capacity can obviate the need for major fa

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Purification Strategies to Process 5 g/L Titers of Monoclonal Antibodies
Altering the order of operations, using new resins, and increasing dynamic binding capacity can obviate the need for major facilty changes.


BioPharm International Supplements


Conclusions

The optimization of operating conditions in platform purification processes allows titers of up to 5 g/L to be accommodated in existing manufacturing facilities. We and others have shown that downstream bottlenecks can be eliminated through the use of conventional purification technologies and the optimization of minor facility equipment.5,10 These platform processes use conventional technologies, including affinity and ion exchange chromatography, without the need for novel unit operations as previously discussed.1,10,11 Chromatography and other standard unit operations offer the benefit of consistent process robustness, high productivity, facilitation of platform processes, low raw material costs compared to the overall cost of manufacturing, and regulatory convenience. Since each antibody may bring its own unique challenges to a platform process, such processes should be flexible where needed while still permitting the use of standard conditions wherever possible.

Acknowledgements

The authors would like to acknowledge Chris Dowd and Nuno Fontes for developing the facility fit model used in sections of this article and Jean Bender for discussions on process fit at multiple manufacturing facilities.

MELODY TREXLER-SCHMIDT, PhD, is a scientist, STEFANIE SZE-KHOO is an engineer, AMBER R. COTHRAN is an engineer, BINH Q. THAI is an engineer, and SANDY SARGIS is a senior research associate, all in late-stage purification; BENEDICTE LEBRETON, PhD, is a scientist, early-stage purification, BRIAN KELLEY, PhD, is vice president, bioprocess development, and GREGORY S. BLANK, PhD, is the director of late-stage purification, all at Genentech, Inc., South San Francisco, CA, 650.225.1956,

References

1. Jagschies G, Grönberg A, Björkman T, Lacki K, Johansson HJ. Technical and economical evaluation of downstream processing options for monoclonal antibody (Mab) production. BioPharm Int. 2006 June (supplement); 10–19.

2. Shukla A, Hubbard B, Tressel T, Guhan S, Low D. Downstream processing of monoclonal antibodies—Application of platform approaches. J Chromatogr B. 2007;848:28–39.

3. Fahrner RL, Knudsen HL, Basey CD, Galan W, Feuerhelm D, Vanderlaan M, Blank GS. Industrial purification of pharmaceutical antibodies: Development, operation, and validation of chromatography processes. Biotechnol Genet Eng Rev. 2001;18:301–27.

4. Swinnen K, Krul A, Van Goidsenhoven I, Van Tichelt N, Roosen A, Van Houdt K. Performance comparison of protein A affinity resins for the purification of monoclonal antibodies. J Chromatogr B. 2007;848:97–107.

5. Gadam S, Bergevin J, Peers D. Basey C. Reconfiguration of a commercial biologics facility to a launch facility for new product introductions: Balancing process and engineering solutions. BioProcess International Conference; 2008 September 23–26; Anaheim, CA.

6. Ghose S, Nagrath D, Hubbard B, Brooks C, Cramer SM. Use and optimization of a dual-flowrate loading strategy to maximize throughput in protein-A affinity chromatography. Biotechnol Prog. 2004;20:830–40.

7. Matthews T, Wolk B. Inline buffer dilution and bioprocess bags: An integrated approach. IBC Biopharmaceutical and Development Manufacturing Summit; 2006 December 6–7; Orlando, FL.

8. Norling L, Chen Q, Blank, G. Establishing Robust Conditions for Clinical and Marketed Products, presented at ACS National Meeting, 2006 September 10–14; San Francisco, CA.

9. Kundu A. Strategies for maximizing clearance of impurities across AEX in the context of an integrated process. ACS National Meeting; 2007 August 19–23, Boston, MA.

10. Kelley B. Very large scale monoclonal antibody purification: The case for conventional unit operations. Biotechnol Prog. 2007;23:995–1008.

11. Kelley B, Blank G, Lee A. Downstream processing of monoclonal antibodies: Current practices and future opportunities. In: Gottschalk U, editor. Process scale purification of antibodies. Hoboken, NJ: John Wiley & Sons; 2009.


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